The National Institute of Neurological Disorders and Stroke sponsored a recent survey of twelve neurological disorders which confirms that the burden of neurologic illness affects many millions of people in the United States. [Hirtz D, Thurman D J, Gwinn-Hardy K, Mohamed M, Chaudhuri A R, Zalutsky R. How common are the “common” neurologic disorders? Neurology 2007 Jan. 30; 68(5): 326-37.] The data indicate that more than two million people in the U.S. (i.e., slightly more than seven per 1,000) have epilepsy. Similarly, more than 35 million individuals live with migraines, a prevalence of 121 out of 1,000.
Likewise, bipolar disorder (BPD) is a prevalent and debilitating manic-depressive illness, affecting approximately 1% of the population worldwide. BPD, a psychosis characterized by cyclic periods of mania and depression, is associated with significant morbidity and mortality, with suicide as a cause of death in as many as 10% of patients. Little is known about the pathogenesis of BPD, but it responds remarkably well to mood-stabilizing drugs, such as lithium ion (lithium), and the anticonvulsant valproate.
Further, as many as 900,000 Americans are infected with the human immunodeficiency virus (HIV). Before the arrival of modern antiviral therapies in the late 1990's, HIV effected rapidly devastating effects on the brain known as HIV-associated dementia (HAD) or neuroAIDS. The current, standard combination of HIV treatments (also known as highly active antiretroviral treatment or HAART) has extended the lives of most U.S. AIDS patients, but has not cured neuroAIDS, despite early reports to the contrary. Current antiviral combinations slow the onset of HIV-related nerve damage that becomes more common the longer HIV patients live. Therefore, whereas patients suffered rapid, severe neurological damage before HMRT therapy, they now gradually lose attention span, memory, speaking ability and decision-making skills despite the best available treatment.
Clinical Uses
Valproic acid (valproate) has been approved by regulatory agencies around the world, including the U.S. Food and Drug Administration (FDA), as a therapy for several clinical indications, including neurological disorders, mania, manic episodes associated with bipolar disorder, epilepsy, and affective and attention deficit disorders. In addition, valproate is used for the prophylactic treatment, modulation and management of migraine headache, chronic pain, and neuropathic pain.
Although the underlying therapeutic mechanisms are unclear, a growing body of evidence suggests that valproate has neuroprotective and neurotrophic actions. For example, both brain imaging and post-mortem studies demonstrate that bipolar disorder involves a decrease in the volume and number of neurons and glia in discrete brain areas thought to be important for cognition and mood regulation. Remarkably, the reduction in brain volume in bipolar patients was found to be largely suppressed by chronic treatment with valproate, in part as a consequence of its histone deacetylase inhibition. [Kanai H, Saws A, Chen R W, Leeds P, Chuang D M. Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neurons. Pharmacogenom J 2004; 4: 336-344.] Likewise, in cellular models, valproate protects rat cerebral cortical neurons and cerebellar granule cells from glutamate-induced excitotoxicity and apoptotic death from stress on the endoplasmic reticulum in C6 glioma cells and PC12 cells. [Bown C D, Wang J F, Chen B, Young L T. Regulation of ER stress proteins by valproate: therapeutic implications. Bipolar Disord 2002; 4: 145-151.] In a rat model of stroke, post-insult valproate treatment reduces ischemia-induced brain damage, caspase-3 activation and neurological deficits. [Ren M, Leng Y, Jeong M, Leeds P R, Chuang D M. Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats: potential roles of histone deacetylase inhibition and heat shock protein induction. J Neurochem 2004; 89: 1358-1367.] A number of studies report that valproate activates cell survival factors such as Akt, extracellular signal-regulated protein kinase, and cyclic AMP response element binding protein. [De Sarno P, Li X, Jope R S. Regulation of Akt and glycogen synthase kinase-3 beta phosphorylation by sodium valproate and lithium. Neuropharmacology 2002; 43: 1158-1164. Yuan P X, Huang L D, Jiang Y M, Gutkind J S, Manji H K, Chen G. The mood stabilizer valproic acid activates mitogen-activated protein kinases and promotes neurite growth. J Biol Chem 2001; 276: 31674-31683. Einat H, Yuan P, Gould T D, Li J, Du J, Zhang L, et al. The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. J Neurosci 2003; 23: 7311-7316.] Additionally, valproate induces cytoprotective proteins such as Bcl-2, Grp78, brain-derived neurotrophic factor, and heat-shock protein 70. [Chen G, Zeng W Z, Yuan P X, Huang L D, Jiang Y M, Zhao Z H et al. The mood-stabilizing agents lithium and valproate robustly increase the levels of the neuroprotective protein bcl-2 in the CNS. J Neurochem 1999; 72: 879-882.] Moreover, valproate promotes neurite outgrowth. [Yuan P X, Huang L D, Jiang Y M, Gutkind J S, Manji H K, Chen G. The mood stabilizer valproic acid activates mitogen-activated protein kinases and promotes neurite growth. J Biol Chem 2001; 276: 31674-31683.] Recently, valproate was shown to protect dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. [Chen P-S, Peng G-S, Li G, Yang S, Wu X, Wang C-C, Wilson B, Lu R-B, Gean P-W, Chuang D-M, Hong J-S. Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Molec Psych 2006; 11: 1116-1125.] Further, valproate at therapeutic levels was reported to inhibit histone deacetylase (HDAC), an enzyme that catalyzes the remove of acetyl groups from lysine residues of histones, thereby altering gene expression. [Phiel C J, Zhang F, Huang E Y, Guenther M G, Lazar M A, Klein P S. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 2001; 276: 36734-36741. Gottlicher M, Minucci S, Zhu P, Kramer O H, Schimpf A, Giavara S et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001; 20: 6969-6978.]
Further, potential therapeutic benefits of valproate in still other clinical indications are being evaluated in on-going clinical trials. Valproate therapy is being evaluated in clinical studies assessing activity of the substance as a histone deacetylase inhibitor to promote cell differentiation and regeneration, or to regulate gene expression in subjects afflicted with spinal muscular atrophy. Likewise, valproate may exhibit therapeutic benefit as a combinatorial therapeutic treatment of human cancers and for the treatment of tumor metastasis. Similarly, valproate may be useful in the treatment and management of pain, for treating severe tinnitus, for treatment of disorders of personal attachment and deficient social interaction, or for treating Alzheimer's disease. Pre-clinical studies also show that valproate may promote neural stem cell differentiation and or be useful as a co-medicament to promote the elimination of the Human Immunodeficiency Virus (HIV) or other retroviruses from the body or to prevent progression of a retroviral infection to AIDS. Clinical investigators have found that both lithium and valproate.
Lithium is indicated for the treatment of bipolar disorder, both for treatment of acute mania and for prophylaxis against recurrence. Other psychiatric conditions that may be benefited by administration of lithium include recurrent severe depressions without manic episodes, schizoaffective psychosis, episodic alcoholism, periodic antisocial behavior, and periodic schizophrenic illness.
Sources of the Active Pharmaceutical Ingredient Valproate
Valproic acid (Chemical Abstracts Service (CAS) Registry No. 99-66-1) is a branched carboxylic acid having the molecular formula C8H16O2. Valproic acid is also known as 2-propylpentanoic acid, 2-propylvaleric acid, and dipropylacetic acid. Valproic acid is a colorless liquid having a boiling point of 120-121° C. at 14 torr. The compound is very slightly soluble in water. It has a pKa of 4.6, and reacts with bases to form salts generally known as valproates.
Although valproate is a therapeutically active pharmaceutical ingredient, valproic acid is an oil that is difficult to formulate and use in the preparation of dosage forms suitable for human or veterinary use. In addition, the administration of valproic acid to subjects requiring its therapeutic administration results in the exhibition of deleterious side effects, including gastrointestinal distress and ulceration. Pharmaceutical and pharmacological advantages are gained when therapeutic dosage forms are prepared from alkali metal or alkaline earth metal salts of valproic acid. Therefore, alkali metal or alkaline earth metal salts of valproic acid are used in present day clinical formulations as sources of the active drug ingredient, valproate.
Sodium (Na1+), calcium (Ca2+) and magnesium (Mg2+) valproates have been evaluated for use in pharmaceutical and veterinary compositions. Sodium valproate is a hygroscopic salt that is difficult to formulate into pharmaceutical formulations. In contrast, non-stoichiometric valproate sodium compounds comprising combinations of sodium valproate and valproic acid (divalproex sodium, for example) are not hygroscopic, and are bioavailable and therapeutically active sources of valproate. (The non-stoichiometric compound known as divalproex sodium is disclosed in U.S. Pat. No. 4,988,731, for example, and one of its therapeutic embodiments is described in the FDA Approved Labeling Text for NDA 21-168, Aug. 4, 2000.) At the present time, divalproex sodium is the most commonly formulated source of the drug valproate.
Calcium valproate has also been evaluated for use in pharmaceutical and veterinary formulations. Methods for the preparation of calcium salts of valproic acid are disclosed in U.S. Pat. No. 4,895,873. Although pharmaceutical formulations comprising calcium valproate have been approved by the regulatory bodies of several countries, the use of this valproate salt has been severely restricted following publication of reports of adverse toxicological and reproductive effects in dogs, rats, mice, rabbits, and rats. (For example, adverse effects caused by calcium valproate administration are reported in “Calcium valproate-induced uterine adenocarcinomas in Wistar rats” by Watkins, Gough, et al. in Toxicology, Vol. 41, pages 35-47, 1993.)
Magnesium valproate is also used in clinical formulations. Magnesium valproate, which has the CAS Registry No. 62859-43-7, a molecular formula of C16H30O4Mg, and a molecular weight of 310.71, is also known as magnesium 2-propylvalerate and as 2-propylpentanoic acid magnesium salt. By weight, its composition is 61.8% carbon, 9.7% hydrogen, 7.8% magnesium, and 20.6% oxygen.
Clinical investigators have reported that magnesium valproate possesses pharmacokinetic properties comparable to sodium valproate or valproic acid, is hydrolyzed to valproic acid and magnesium ions upon absorption in the bloodstream, and has important advantages in comparison with either sodium valproate or valproic acid. Among the therapeutic advantages of magnesium valproate are the clinical observations that magnesium valproate exhibits a slower and more regular absorption rate, which prevents the variations in plasma levels of valproate typically observed when sodium salts of valproic acid are administered. Additional therapeutic benefits are afforded by magnesium ions, which possess anticonvulsant and sedative properties. [X. Rabasseda, Drugs of Today, Vol. 31, No. 3, 1995, pp. 185-190.] In contrast to calcium valproate, which exacerbates malignancy, magnesium valproate is a useful therapy when administered to patients with cervical cancer. For example, Chavez-Blanco et al. have reported that magnesium valproate at a dose between 20 and 40 mg/kg inhibits deacetylase activity and hyperacetylates histones in tumor tissues. [A. Chavez-Blanco, B. Segura-Pacheco, et al., Molecular Cancer Jul. 7, 2005, Vol. 4, pp. 22ff.]
Sources of the Drug Lithium
Lithium is most frequently administered therapeutically for the treatment of neurological dysfunction as lithium carbonate, a white, low-melting powder that is slightly soluble in water and alcohol. Lithium carbonate has a Chemical Abstracts Registry No. of 554-13-3, a molecular formula of Li2CO3, and a molecular weight of 73.89.
There is no commercial source of lithium valproate. No Chemical Abstracts Registry Number has been assigned to lithium valproate. Its physico-chemical properties have not been reported.
Polytherapy with Lithium and Valproate
Recently there has been a great deal of interest in the use of combinations of therapeutic agents, i.e., “polytherapies,” in the treatment of neurological disorders. In routine practice for acute mania, both lithium and valproate, administered as separate entities, are useful as adjuncts to antipsychotic drugs, rather than as monotherapy. The antipsychotic activity of valproate is exhibited relatively quickly after therapeutic doses are administered. In contrast, lithium has a delayed effect, taking a few days to begin, and 2-8 weeks or longer to approach its full effect on mania.
Lambert and other French investigators have reported beneficial therapeutic responses to the concomitant administration of valproate (administered as valpromide) and lithium for the treatment of patients with major affective disorders and schizophrenia. [P. A. Lambert. Acute and prophylactic therapies of patients with affective disorders using dipropylacetamide or valpromide. Proceedings of the 7th World Congress of Psychiatry, Vienna, Jul. 11-16, 1983. G. W. Semadeni. Etude clinique de l'effet normothymique du di-propylacetamide. Acta Psychiatr Belg 1976; 76: 458-466.] That response permitted a reduction in the dosage levels of the psychotropic agent required to maintain optimal improvement, which in turn reduced the overall risk of adverse experiences. Further, long-term administration of combinations of valproate and lithium suggested that these two agents may exert a synergistic effect in bipolar patients that is particularly useful in patients whose symptoms are inadequately controlled by lithium alone. Moreover, the adverse effects observed with the concomitantly administered combination were typically only those noted with the use of either individual agent. No unique adverse effects occurring as a result of the drug combination were reported.
Hayes has completed a retrospective study of clinical cases in which valproate [as Depakote® (sodium hydrogen divalproate; Abbott Laboratories, Inc., McGaw Park, IL] or combinations of valproate and lithium were administered to 35 patients, all with major depressive illness, bipolar disorder, or schizoaffective disorder, were retrospectively identified as having received valproate either alone or in combination with lithium, after having failed to respond adequately to previous lithium and/or carbamazepine treatment. [S. G. Hayes, M. D. Long-term valproate use in psychiatric disorders. J. Clin Psychiatry 50 (3, Suppl), pages 35-39.] Clinical evaluation and Global Assessment Scale (GAS) scores indicated that at baseline all but 3 of the patients experienced serious psychiatric symptoms, serious impairment in social or professional functioning, or significant impairment in reality testing. Mean GAS scores after a mean duration of at least 1 year of valproate administration improved in 7 of 9 depressed patients, 12 of 12 patients with bipolar disorder, and 11 of 14 patients with schizoaffective states. For patients with either depressive disorders or mixed bipolar disorders, that mean change represented a level of improvement sufficient to elevate the majority of the patients into the mild symptom range or the virtually asymptomatic state. Patients with bipolar and schizoaffective disorders to valproate treatment compared to valproate plus lithium were evaluated for an average of 11 to 14 months of treatment. Patients in both treatment groups demonstrated very similar and quite substantial improvement in mean change in GAS ratings (35.0 and 33.8, respectively, for the valproate and valproate+lithium groups) and global evaluations, regardless of whether valproate was administered alone or in combination with lithium. As an anecdotal observation, certain patients did respond better to the combination of valproate and lithium, although this response did not happen frequently enough to reach statistical significance.
Over the past two decades, clinicians increasingly have used concomitant administration of a lithium drug and valproate, optionally with a third drug, to beneficially mitigate the mania and depression associated with BPD. For example, Sharma et al. reported treatment of rapid cycling BPD with combination therapy of valproate and lithium. [V. Sharma, E. Persad, D. Mazmanian, K. Karunaratne. Treatment of rapid cycling bipolar disorder with combination therapy of valproate and lithium. Can. J. Psychiatry 1993; 38: 137-139.]
In U.S. Patent Application 2005/0233010 Salow discloses combinatorial therapies for treating anxiety, depression or psychotic conditions using a co-therapy regimen comprising a lithium salt and a psychoactive drug selected from the group consisting of serotonin reuptake inhibitor, a 5HT2 receptor antagonist, an anticonvulsant, a norepinephrine reuptake inhibitor, an α-adrenoreceptor antagonist, an NK-3 antagonist, an NK-1 receptor antagonist, a PDE4 inhibitor, a neuropeptide Y5 Receptor Antagonist, a D4 receptor antagonist, a 5HT1A receptor antagonist, a 5HT1D receptor antagonist, a CRF antagonist, a monoamine oxidase inhibitor, a sedative-hypnotic drug, and an atypical psychotic. Exemplary forms of lithium salts include lithium carbonate, lithium citrate, lithium acetate, lithium glutamate, lithium orotate, lithium thionate, and lithium sulphate. Valproate is named as an anticonvulsant drug that may be co-administered with a lithium salt.
Lithium valproate has not, however, been available for clinical use. In the absence of lithium valproate, clinicians and patients have noted the following serious difficulties in treatment management. Concomitant administration of lithium with other antipsychotic drug(s) can unexpectedly increase intracellular lithium levels, a possible mechanism for unanticipated adverse interactions and resulting toxicity. Patients with bipolar disorder demonstrate poor compliance with dosing regimens that included two different drugs (i.e., a lithium drug and a valproate drug) and/or two different dosing regimens and suffer the occurrence of withdrawal mania. Poor compliance with the aforementioned dosing regimens also increases the risks of side effects and toxicity, including the possibility of permanent neurological sequelae with cerebellar damage. (Valproate toxicity includes dizziness; elevated SGPT, SGOT, alkaline phosphatases, and LDH values; and sedation and/or nausea. Lithium toxicity includes the potential for extrapyramidal side-effects, cogwheel rigidity, cerebellar tremor, incoordination, severe neurological symptoms, hyperthermia, impaired consciousness and irreversible brain damage. [J. C. Cookson. The neuroendocrinology of mania. J Affect Disorders 1985; 8:233-241. M. Schou. Long-lasting neurological sequelae after lithium intoxication. Acta Psych. Scand. 1984; 70: 594-602.]
Among the drugs that have been studied as potential treatments for HAD are antioxidant medications, calcium channel antagonists, NMDA antagonists, platelet activating factor inhibitors, and drugs that inhibit glycogen synthase kinase 3 beta (GSK-3β) and mixed lineage kinase (MLK). Specifically, sodium valproate and lithium ion, existing epilepsy drugs, have proven to be GSK-3β inhibitors having strong potential as treatments for HAD. Schifitto et al., for example, conducted a pilot 10-week placebo-controlled study of valproate (250 mg twice daily) in 22 HIV-infected individuals with (n=16) and without (n=6) cognitive impairment. [G. Schifitto, D. R. Peterson, J. Zhong, H. Ni, K. Cruttenden, M. Gaugh, H. E. Gendelman, M. Boska, and H. Gelbard. Valproic acid adjunctive therapy for HIV-associated cognitive impairment. A first report. Neurology 2006.) Valproate was safe and well tolerated, with trends toward improved neuropsychological performance and brain metabolism in the impaired subjects.
In brief, clinicians have shown that both lithium (ion) and valproate are useful drugs for the treatment of neurological disorders. To date, however, the lack of availability of lithium valproate as a stable, non-hygroscopic valproate salt has prevented broader therapeutic applications of lithium valproate. The present invention remedies these shortcomings.